Attention clinicians

The Clinical Practice Guideline on which this Quick Reference Guide for Clinicians is
based was developed by an interdisciplinary, private- sector panel comprising health
care professionals and consumer representatives. Panel members were:

Note: This Quick Reference Guide for Clinicians contains excerpts from the Clinical
Practice Guideline, but users should not rely on these excerpts alone. Clinicians
should refer to the complete Clinical Practice Guideline for more detailed analysis and
discussion of the available research, critical evaluation of the assumptions and
knowledge of the field, health care decision making, and references.

Purpose and Scope

Sickle cell disease comprises a group of genetic disorders characterized by the
inheritance of sickle hemoglobin (Hb S) from both parents or Hb S from one parent
and a gene for an abnormal hemoglobin or beta- thalassemia from the other parent.
The presence of Hb S can cause red blood cells to change from their usual biconcave
disc shape to a crescent or sickle shape during deoxygenation. Upon reoxygenation,
the red cell initially resumes a normal configuration, but after repeated cycles of
"sickling and unsickling," the erythrocyte is damaged permanently and hemolyzes.
This hemolysis is responsible for the anemia that is a hallmark of sickle cell
disease. The following table includes the most common types of sickle cell disease.

Acute and chronic tissue injury can occur when blood flow through the vessels is
obstructed by the abnormally shaped red cells. Complications include painful
episodes involving soft tissues and bones, acute chest syndrome, priapism, cerebral
vascular accidents, and both splenic and renal dysfunction. Common causes of
mortality among children with sickle cell disease include bacterial infections,
splenic sequestration crisis, and acute chest syndrome.

Sickle cell disease affects more than 50,000 Americans, primarily those of African
heritage, but also those of Mediterranean, Caribbean, South and Central American,
Arabian, or East Indian ancestry. It is estimated that 8 percent of the African
American population carries the sickle cell trait, and approximately 1
African-American child in every 375 is affected by sickle cell disease. Thus, it is
among the most prevalent of genetic diseases in the United States.

This Quick Reference Guide contains excerpts from the Clinical Practice Guideline on
Sickle Cell Disease: Screening, Diagnosis, Management, and Counseling in Newborns
and Infants. Clinicians should not rely on this summary alone but should refer to
the Clinical Practice Guideline for a more complete discussion of issues and
recommendations.

The algorithm, found on pages 8 and 9 of this Quick Reference Guide , shows the
sequence of events related to sickle cell screening, diagnosis, medical management,
and counseling in newborns and infants. This Quick Reference Guide provides
information about the events listed in the algorithm.

Types of Sickle Cell Disease

Sickle cell anemia

S-O Arabr

Hemoglobin SC disease

S-Lepore

Sickle beta-thalassemia

S-E disease

S-D Punjab

Guiding principles

All infants should be screened for sickle cell disease, regardless of
race or ethnic background.

Sickle cell screening must be done by accurate laboratory methods.

Physicians must establish a definitive diagnosis in a timely fashion for
infants with a positive screening test.

Affected infants and parents must have access to comprehensive health
care services, including education and decision-making counseling.

Neonatal sickle cell screening programs also provide an opportunity to
identify other members of the family with sickle cell trait and other
abnormal hemoglobins. When these individuals are found, clinicians
should offer them education and genetic counseling.

Screening

Neonatal screening programs for sickle cell disease should be comprehensive. Such
programs require the integration of several components, including administration,
laboratory, medical management, and education/counseling.

Administration

The administrative component should oversee the entire program, monitoring the
efficacy of the screening initiative, the quality and accuracy of laboratory
testing, the diligence of medical followup, and the activities of the education and
counseling program.

The administrative group should include public health officials; geneticists;
representatives from the laboratory; staff from the education and counseling
program; physicians knowledgeable about sickle cell disorders, thalassemia, and
other hemoglobinopathies; and when possible, representatives of community-based
sickle cell organizations.

Population To Be Screened

Universal screening is the only way to ensure that all infants benefit equally and
that no infant is subjected to the risk of early death from sickle cell disease
because the screening test was not performed.

Screening programs targeting a specific racial or ethnic group will not identify all
infants with sickle cell disease, because it is impossible to define reliably an
individual's racial or ethnic background by physical appearance, surname, or
self-report.

Laboratory Issues

Blood Samples

To obtain reliable results, blood samples for sickle cell screening
must be collected prior to transfusion.

Blood samples collected from the infant by heel stick onto filter
paper are preferred for sickle cell screening because shipment to
the laboratory is easy. This collection method is currently employed
for other screening programs including those for phenylketonuria,
hypothyroidism, and galactosemia.

Liquid blood samples, obtained from the umbilical cord or directly
from the infant, are acceptable alternatives but are more expensive
and difficult to transport to the screening laboratory.

Testing Methods

Hemoglobin electrophoresis, isoelectric focusing, and high
performance liquid chromatography are all proven, reliable, and
accurate methods for defining an infant's hemoglobin phenotype.

Globin DNA analysis is an additional testing method, though this
method requires considerable expertise and is costlier than the more
established methods.

The methods chosen for screening newborns should have high rates of
sensitivity and specificity for identification of newborns with
sickle cell disease and other clinically important
hemoglobinopathies.

Note: Neither the sodium metabisulfite sickle cell preparation nor solubility
tests employing a concentrated phosphate buffer and sodium dithionate should be
used for newborn screening or confirmation of Hb S in early infancy.

Laboratory Qualifications

All testing should be done by laboratories that are licensed by their respective
States or territories and that meet the requirements of the Clinical Laboratory
Improvement Act of 1988 (CLIA 88).

Laboratory testing should be linked to other existing newborn screening programs
within the jurisdiction to facilitate specimen collection, identification, handling,
and result reporting.

Quality Assurance and Quality Control

The screening program must monitor all aspects of the screening process from sample
collection to confirmation of diagnosis and tracking of infants to ensure that those
with positive screening tests are retested and that infants with confirmed diagnoses
are entered into comprehensive care.

Laboratories must participate in a proficiency testing program and, when feasible,
should retest at least a sample of all newborns screened to determine the
sensitivity and specificity of its screening methodology.

Reporting of Screening Results

Screening laboratories should maintain accurate records and are responsible for
promptly communicating test results to the infant's health care provider of record,
hospital of birth, the screening program's administrative component, and when
permitted by law, to the infant's mother.

Reporting of the screening result should include the hemoglobin phenotype and
mention the diagnostic possibilities associated with the phenotype. Reports to
health care providers and mothers should list sources of additional information. The
report must clearly indicate the likelihood that the infant may have sickle cell
disease and stress the urgency for immediate followup.

Medical Management

Responsibilities of Health Care Providers

Assignment of definitive diagnosis is the responsibility of the
infant's physician. Physicians unfamiliar with diagnostic criteria
should seek consultation from hematologists knowledgeable about
sickle cell disease, thalassemia, and other hemoglobinopathies.

When a newborn tests positively for sickle cell disease or other
hemoglobinopathy, health care providers should immediately contact
the parents to inform them of the need for the infant's immediate
evaluation and retesting.

Since newborn screening does not establish a definitive diagnosis, a
second sample must be collected from the infant. In addition to
defining the hemoglobin phenotype, the second specimen should be
used to determine a complete blood count with red cell indices and
assessment of red cell morphology.

Characterization of the hemoglobin phenotype of the parents can be
extremely helpful. The clinician must be aware that testing of the
parents may disclose nonpaternity.

DNA analysis of the infant's beta globin gene complex also may be
used to establish a definitive diagnosis.

Physicians and other health care providers must be aware that any
sign of illness in an infant with sickle cell disease is a potential
medical emergency. Complications of sickle cell disease include, but
are not limited to sepsis, acute chest syndrome, splenic
sequestration crisis, aplastic crisis, stroke and hand-and-foot
syndrome, and painful episodes.

The physician or other health care provider is responsible for
providing or arranging for appropriate education and genetic
counseling for the parents.

Prophylactic Penicillin

Infants with documented or suspected sickle cell anemia or Hb S
betao-thalassemia should be started on twice-daily
oral prophylactic penicillin as soon as possible, but no later than
2 months of age.

In those instances where the definitive diagnosis cannot be
determined, an infant with the FS phenotype should be maintained on
prophylactic penicillin until the definitive diagnosis is
established.

Prophylactic penicillin should be continued until at least 5 years
of age.

Well-Baby Care

Infants with sickle cell disease should receive standard well baby
care. In addition to immunizations against polio, diphtheria,
tetanus, measles, mumps, and rubella, children with sickle cell
disease should be immunized against Haemophilus influenzae beginning
at age 2 months and should receive polyvalent pneumococcal vaccine
at age 2 years. Infants also should be immunized against hepatitis B
virus.

Diet should be monitored to ensure that the child with sickle cell
disease is receiving all necessary nutrients and adequate calories.
Multivitamins during the first 2 years of life may be appropriate.

Parental Instruction

Health care providers must stress to parents the importance of
twice-daily doses of prophylactic penicillin as an effective measure
to reduce both morbidity and mortality from pneumococcal infections
in infants with sickle cell anemia and Hb S
betao-thalassemia.

Parents of infants with sickle cell disease should be instructed in
all aspects of routine child care and should be able to determine
accurately the infant's temperature. They must be able to recognize
complications of sickle cell disease, including the signs and
symptoms of fever, pallor, and respiratory distress. Parents should
be instructed on palpation of the infant's spleen and be taught to
recognize splenic enlargement.

The parents must understand the importance of prompt assessment of
the infant by a physician knowledgeable about sickle cell disease
when there is fever, pallor, unexplained irritability, diarrhea,
vomiting, or other signs of illness.

Access to Care

Acutely ill infants with sickle cell disease should have access to
tertiary care facilities that are staffed by pediatricians and
pediatric surgeons knowledgeable about sickle cell disease.

These facilities should include a sophisticated blood bank and
clinical laboratories, as well as modern imaging equipment.

Education and Counseling

Principles

A neonatal sickle cell screening program not only identifies infants
with sickle cell disease, but also opens a "genetic window," which
can result in the detection of other family members with sickle cell
trait, sickle cell disease, or other hemoglobin diseases and
heterozygotes for hemoglobin variants.

Screening programs have an obligation to inform parents regarding
their infant's result and to offer related education and counseling.

Screening provides an invaluable opportunity to educate and counsel
families.

Education

Sickle cell education should include an explanation of the
differences between the disease and the trait, prevalence of sickle
cell trait and anemia in the U.S. population, the health status of
persons with sickle cell trait, and the risks of having a child with
sickle cell disease for persons with the trait.

Information should be presented clearly using interactive techniques,
appropriate graphics, and plain language. Easily understandable
literature should be given to the parents to take home at the end of
the education session.

Parents should be offered the opportunity to be tested if they so
desire. All adults testing positive for either Hb S,
betao-thalassemia trait, or a variant hemoglobin and
those who have partners with either of these conditions also should
be offered decision-making counseling.

At a minimum, sickle cell educators should have a high school
diploma and a certificate of competency in sickle cell education.
The certifying process should be approved by the administrative
component of the screening program and include successful completion
of an examination that assesses knowledge of the material.

The educator's skills should be evaluated periodically, and their
sickle cell knowledge base should be updated annually.

Decision-Making Counseling

Decision-making counseling should provide objective information about
sickle cell disease and trait to individuals who are at risk of
having a child with sickle cell disease. It should include specific
information on the natural history of the type of sickle cell
disease that may affect the individual's offspring and the resources
that may be required to care for the child. This empowers the
prospective parents to make informed decisions.

Decision-making counseling must always be objective and should not
offer specific recommendations. The counseling atmosphere must be
private and conducive to a free exchange of information.

Counseling should be done by professionals with backgrounds and
training in guidance and counseling, such as physicians, clinical
geneticists, genetic associates, medical social workers, and nurses.

Quality assurance is an essential component of a genetic counseling
program.

Conclusion

Although the prevalence of hemoglobin disorders differs among racial and ethnic
groups, it is impossible to define reliably an individuals' race or ethnicity in a
heterogeneous society like the United States. It is therefore recommended that
screening programs provide equal access to health care by screening all infants for
sickle cell disease and other hemoglobinopathies.

Screening programs should reduce costs through cooperative arrangements negotiated
with other programs or with institutional or commercial laboratories to obtain the
lowest cost per test for universal sickle cell screening.

Algorithm

The algorithm on pages 8 and 9 presents a visual display of the organization,
procedural flow, and decision points in identifying and caring for newborns and
infants with sickle cell disease, sickle cell trait, and other hemoglobinopathies
and educating and counseling their parents. Numbers in the algorithm refer to the
annotations that follow. Detection and Management of Sickle Cell Disease: An
Algorithm [ Figure 1.]

Universal screening

1. The panel concluded that universal newborn screening should be conducted to
detect sickle cell disease. This conclusion is based both on considerations of
practicality and cost-effectiveness. Screening for hemoglobinopathies should be
conducted in parallel with other conditions routinely screened for in newborns.

Performed in laboratories meeting appropriate standards

2. The panel concluded that sickle cell screening should be performed only in
laboratories that meet appropriate standards of performance and reporting.
Quality assurance activities and appropriate reporting practices are discussed
in Chapter 2.

The panel concluded that any of three methods are acceptable for sickle cell
screening: (1) hemoglobin electrophoresis, (2) isoelectric focusing, and (3)
high performance liquid chromatography. All are considered reliable and
accurate. Metabisulfite sickle cell preparations and solubility testing,
however, are not acceptable screening methods for newborns and should not be
used to confirm the presence of hemoglobin S in newborns and infants.

Blood samples for testing may be submitted as anticoagulated blood from the
umbilical cord or as dried blood spots collected onto filter paper. Each method
has advantages and disadvantages. Filter paper samples are more easily
integrated into existing newborn screening programs.

Abnormality detected?

3-4. The common types of sickle-cell abnormalities are discussed in Chapters 1
and 2.

Parents of sickle cell trait infants should be offered education and counseling.
Couples at risk for having an infant with sickle cell disease should be offered
decision-making counseling.

Other disease?

Parents of infants with other diseases or heterozygote conditions should be
offered education and counseling. Couples at risk for having a child with
disease should be offered decisionmaking counseling.

5. The presence of another abnormal hemoglobin may warrant referral for medical
care. Parents of children with trait should receive counseling. These issues are
discussed in Chapters 1, 2, and 4.

Appropriate reporting

6. Reporting of preliminary screening results is discussed in Chapters 2 and 3.

Initiation of comprehensive care including penicillin prophylaxis and
immunization

7. Children with sickle cell disease identified on screening examination should
be referred to a comprehensive care program without delay. Because confirmatory
testing may not be complete for several weeks or months, it is important not to
delay the basic elements of care, as described in nodes 9-12.

The panel concluded that prophylaxis against pneumococcal infection is warranted
in all children with sickle cell anemia and sickle betao-thalassemia.
Administration of twice-daily oral penicillin has been demonstrated to reduce
morbidity and mortality in these children. Children with sickle cell anemia also
are at high risk for pneumococcal and Haemophilus influenzae infections.
Immunization is extremely important (Chapter 3) and should be initiated by 2
months of age.

Confirmatory testing positive?

8. All positive screening tests for sickle cell disease require a second blood
sample to confirm the initial hemoglobin phenotype. A definitive diagnosis
should be established by the infant's physician.

Counseling and education of parents

9. Parents of infants with sickle cell disease must be counseled concerning the
implications of their child's condition. Specifically, parents should be
informed about the need for close vigilance with respect to the development of
signs and symptoms that could indicate a serious medical problem. Any of the
following warrant immediate medical consultation: (1) fever, (2) symptoms of
respiratory tract infection, (3) increasing pallor, (4) increasing spleen size
or abdominal distension, (5) weakness or numbness of an extremity, and (6)
painful swelling of hands and feet. Information also should be provided
concerning diet and adequate hydration. Parents should be trained in home
management skills and should receive genetic counseling (Chapters 3 and 4).

Health maintenance and compliance

10. The schedule of health maintenance visits need not differ from that used for
a well child. Strenuous efforts must be made by the health care provider to
ensure compliance with penicillin prophylaxis (Chapter 3).

Parent presents child for emergency care?

11. Parents should be encouraged to seek immediate medical attention whenever
the warning signs described in node 12 are noted.

Patient febrile?

12. Fever over 101 degrees F (38.5 degrees C) requires immediate medical
evaluation. The parent also should be told that changes in behavior (unusual
somnolence or irritability) or alimentation (refusing feeding, vomiting or
diarrhea) are other possible early signs of significant illness.

Consider sepsis

13. It is critical that all health care providers who care for patients with
sickle cell disease be knowledgeable about the significance of fever in these
children. The importance of evaluating febrile sickle cell children promptly and
administering broad spectrum antibiotics are emphasized. Management of febrile
children with sickle cell disease is discussed in Chapter 3.

Pallor, lethargy, and abdominal symptoms?

14-15. Acute anemia emergencies are common in children with sickle cell disease,
particularly acute splenic sequestration and aplastic crises. Diagnosis and
management of these conditions are discussed in Chapter 3.

Limping, paresis, or other symptoms compatible with stroke?

16-17. Although relatively infrequent, both parents and providers must be alert
for the possibility of a stroke. Any loss of consciousness or weakness of an
extremity should be evaluated promptly.

Painful swelling of hands and feet?

18-19. The most frequent early complication of sickle cell disease is the
hand-and-foot syndrome, or dactylitis (Chapter 3).

Note: All chapter references are to the complete Clinical Practice Guideline,
Sickle Cell Disease: Screening, Diagnosis, Management, and Counseling in
Newborns and Infants.